Formulations and Methods for Modulating Satiety

Abstract

This disclosure relates to formulations and methods of suppressing appetite and eliciting satiety (sense of being filled) in mammals through the oral administration of an effective amount of an appetite suppressing moiety.

Description

TECHNICAL FIELD OF THE INVENTION[0001]The invention relates to the field of appetite management and suppression. More specifically, the invention relates to methods, compositions for modulating satiety and thus, to approaches useful to control weight, especially to manage excess weight and obesity.BACKGROUND OF THE INVENTION[0002]Excess weight, ranging from being overweight to obesity and culminating in morbid obesity, is a major concern for industrialized nations because of the deleterious health effects overweight and obesity have been associated with. Overweight and obesity are diseases of excess energy stores in the form of fat. Overweight individuals have a Body Mass Index (BMI) of between 26 kg / m2 and 30 kg / m2 and obese individuals have a BMI of between 30 kg / m2 and 40 kg / m2. Moreover, morbid obesity (this term is synonymous with “clinically severe obesity”) correlates with a Body Mass Index (BMI) of at least 40 kg / m2 or with being 100 pounds overweight.[0003]The most obvious ...

AI Technical Summary

Benefits of technology

[0017]The invention is based on the unexpected and surprising discovery that certain appetite suppressing (satiety) moieties associated in the literature with sub-therapeutic oral bioavailability may be orally bioavailable when formulated as described herein. The invention further provides methods of administering such formulations to enhance bioavailability. The invention also provides methods of using such formulations in a patient to treat various conditions. As exemplified, the pharmaceutical formulations and methods according to the invention are shown to modulate / induce satiety and reduce feeding as evidenced by a marked weight loss in treated patients as compared to those untreated.

[0018]Accordingly, it is an object of the present invention to provide pharmaceutical formulations suitable for oral administration. Another object of the present invention is to reduce the caloric intake in treated patients by the oral administration of the formulations according to the invention. Yet another object of the invention is to cause weight loss resulting from a reduced caloric intake. In some patients, an object of the invention is to manage weight (and in some instances to preserve weight) by modulating appetite, and thus caloric intake, by the oral administration of appetite suppressing (satiety) peptides formulated according to the invention.

[0019]Another aspect of the invention is to provide formulations and methods to provide better glycemic control for Type II diabetics. An object of the invention is thus, to help Type II diabetics to enhance and extend satiety. Another object is thus to reduce caloric intake in Type II diabetics. In another aspect, the invention provides formulations and methods to increase satiety in bulimics who have a defect in their normal CCK release mechanism.

Problems solved by technology

Lack of respect for the morbidly obese is also an issue of concern.

There are widespread negative attitudes that the morbidly obese adult is weak-willed, ugly, awkward, self-indulgent and (in somefora, even as much as immoral).

This can promote psychological distress and increase the risk of developing a psychological disorder.

Overweight and obesity have become a public health epidemic.

Unfortunately, the CDC also reports that the problem is getting worse and that in 2000 the cost of obesity in the United States was more than $117 billion (Overweight and Obesity: Frequently Asked Questions [online], June 2004 [retrieved on Jul. 05, 2004]; retrieved from the Internet: ).

The many manifestations of diets and exercise routines have worked to some degree for some individuals but have ultimately failed the population as a whole.

Diets are often difficult to maintain and may place the patient in danger if done incorrectly, leading to a “yo-yo” of weight gain and weight loss.

For example, such a “yo-yo” effect places a strain on the patient's cardiovascular system.

Surgical treatments have met some measure of success but are invasive and in some cases fatal.

Assessing the risks of surgical treatment of obesity involves operative, perioperative and long term complications.

In the late postoperative period, other problems may arise and may require reoperation.

Gastric bypass treatments, however, are only appropriate for those with a BMI of 40 kg / m2 or greater (Yanovski et ail., 2002, N. Engl. J. Med. 346:591-602).

Unfortunately, the average weight loss is a relatively insignificant ranging from 5 to 22 pounds when compared to a target loss of 100 or more pounds.

Some medications, like Orlistat and Sibutramiine (sold under the trademarks XENICAL and MERIDIA respectively), are indicated for long term use but may have considerable risks associated with their use.

Combination therapies have also been employed with some success but often with serious consequences.

For example, the appetite suppression cocktail fenfluramine and phentermine (“fen / phen”) has been withdrawn from the market due to fatalities attributed to fenfluramine.

In addition, many of these medications are controlled substances and may have other serious side-effects that include the potential for dependence and the development of tolerance to the medication (National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

While each of these lines of attack may be successful in some individuals, there remains a considerable portion of refractory patients in need of new alternative methodologies.

Although the consensus is that peripherally administered CCK as well as caerulein is able to reduce food intake in man, the mechanism by which this effect is brought about have not definitively been elucidated.

Both effects, which result in a deceleration of gastric emptying lead to gastric distension when more food is ingested decreasing overall intake.

It has been discovered that CCK and caerulin, like many other peptides cannot be effectively administered by the oral route because of intestinal metabolism and poor systemic absorption from the gastrointestinal tract.

To be effective, CCK and caerulein would need to be administered via intravenous or intramuscular routes, requiring intervention by a physician or other health care professional, entailing considerable discomfort and potential local trauma to the patient.

Notably, the art fails to identify suitable formulations or specific treatment regimens and schedules which would render the target agents therapeutically effective upon oral administration.